Covalent modification of cellular substrates with methyl groups has been implicated in the pathology of cancer and other diseases (Gloria, L. et al. (1996) Cancer 78:2300-2306). Cytosine hypermethylation of eukaryotic DNA prevents transcriptional activation (Turker, M. S. and Bestor, T. H. (1997) Mutat. Res. 386:119-130). N.sup.6 -methyladenosine is found at internal positions of mRNA in higher eukaryotes (Bokar, J. A. et al. (1994) J. Biol. Chem. 269:17697-17704). Hypermethylated viral DNA is transcribed at higher rates than hypo- or hemimethylated DNA in infected cells (Willis, D. B. et al. (1989) Cell. Biophys. 15:97-111).
Many pathways of small molecule degradation, such as those of neurotransmitters, require methyltransferase activity (Kagan, R. M. and Clarke, S. (1994) Arch. Biochem. Biophys. 310:417-427). Degradation of catecholamines (epinephrine or norepinephrine) requires phenylethanolamine N-methyltransferase. Hydroxyindole methyltransferase converts N-acetyl-5-hydroxytryptarnine to melatonin in the pineal gland.
S-adenosylmethionine (AdoMet) is an important source of methyl groups for methylation reactions in the cell (Bottiglieri, T. and Hyland, K. (1994) Acta Neurol. Scand. Suppl.154:19-26). Methyltransferase activity catalyzes the transfer of methyl groups from AdoMet to acceptor molecules such as phosphotidylethanolamine or the polynucleotide 5' cap of viral MRNA (Montgomery, J. A. et al. (1982) J. Med. Chem. 25:626-629).
Members of the S-adenosylmethionine methyltransferase family (AdoMet-MT), utilize AdoMet as a substrate or product and harbor three common consensus sequence motifs. Motifs I and II are characteristically spaced between 34 and 90 (mode 52, median52-54) amino acid residues apart; motifs II and III are spaced between 12 and 38 (mode 22, median 20-22) residues apart. Motif I comprises part of the AdoMet binding pocket; motif II may also be involved in binding AdoMet; the role of motif III is uncertain (Kagan, R. M. and Clarke, S. (supra)).
Messenger RNA N.sup.6 -adenosine methyltransferase holoenzyme has been partially purified from HeLa cell nuclear extract to yield three subunits, an 875 kDa ssDNA-agarose binding protein, a 70 kDa AdoMet-binding protein, and an approximately 30 kDa component with unknown function. The three components are absolutely required for RNA m.sup.6 A-methylation activity (Bokar, J. A. (supra)).
The nematode Caenorhabditis elegans employs many of the same methyltransferase activities found in higher animals (Kagan, R. M. and Clarke, S. (1995) Biochemistry, 34:10794-10806). A C. elegans C27F2 gene product identified as a member of the methyltransferase family has now been described (Wilson, R. et al. (1994) Nature 368:32-38).
In their roles as a rate-limiting step in methyltransferase reactions, AdoMet-MTs have been identified as a target for psychiatric, antiviral, anticancer and anti-inflammatory drug design (Bottiglieri, T. and Hyland, K. (supra); Gloria, L. et al. (supra)). Sequence-specific methylation inhibits the activity of the Epstein-Barr virus LMP 1 and BCR2 enhancer-promoter regions (Minarovits, J. et al. (1994) Virology 200:661-667). 2'-5'-linked oligo(adenylic acid) nucleoside analogues synthesized by interferon-treated mouse L cells act as antiviral agents (Goswarmi, B. B. et al, (1982) J. Biol. Chem. 257:6867-6870). Adenine analogue inhibitors of AdoMet-MT decreased nucleic acid methylation and proliferation of leukemia L1210 cells (Kramer, D. L. et al. (1990) Cancer Res. 50:3838-3842).
The discovery of a new human S-adenosyl-L-methionine methyltransferase and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of neoplastic, immunological, and vesicle trafficking disorders.